Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes.

Abstract

Insulin-like growth factors (IGFs) circulate attached to binding proteins (IGFBPs). Only the unbound form of IGF is suggested to be biological active. The main source of circulating IGF-I and IGFBP-1 is considered to be the liver, but that of circulating IGFBP-3 is not known. IGF-I and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. The aim of the present study was to examine the effect of insulin on the hepatic secretion of IGFBP-1, IGFBP-3, and IGF-I. Seven insulin-dependent diabetic patients in whom insulin was withheld for 12 h were studied in the overnight fasted state. Blood was sampled simultaneously from the hepatic vein, a peripheral vein, and an artery before and during insulin infusion for 3 h. The basal IGFBP-1 levels in the peripheral vein were several-fold elevated (249 +/- 44 micrograms/L) compared to those in healthy subjects (37 +/- 2 micrograms/L). Fasting IGFBP-1 concentrations were inversely correlated to the insulin levels (r = -0.918; P < 0.001). The mean IGF-I concentration (175 +/- 17 micrograms/L; -1.62 +/- 0.38 SD score) was decreased compared with that in age-matched healthy subjects. The basal IGFBP-3 levels in the peripheral vein (4.50 +/- 0.33 mg/L) were within the normal range. There was a significant correlation in the hepatic vein between fasting IGF-I and IGFBP-3 levels (r = 0.928; P < 0.001). Basal splanchnic IGFBP-1 production was 18 +/- 7 micrograms/min, whereas no basal net exchanges of IGF-I or IGFBP-3 were observed across the splanchnic area. Insulin inhibited splanchnic IGFBP-1 production within 120 min and glucose output within 20 min. Serum IGF-I, but not IGFBP-3, concentrations increased significantly during the insulin infusion. In summary, this study demonstrates the existence of considerable IGFBP-1 production from the liver during insulinopenia and the complete blocking of splanchnic IGFBP-1 production and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels. Thus, insulin may play a role in determining the bioavailability of IGF-I.

Insulin-Like Growth Factors (IGFs) and IGF-Binding Proteins (IGFBP-1, -2 and -3) in Diabetic Pregnancy: Relationship to Macrosomia.

“…Although glucose is not a direct stimulator of IGFs in postnatal life, insulin has been shown to stimulate IGF-I production in adults [28]. The present study revealed a positive correlation between umbilical IGF-II levels and placental weight in diabetic pregnancy.…”

“…In addition, we found that they were significantly higher in IDDM mothers and their infants. Recent studies have shown that serum IGFBP-1 levels are, at least in part, regulated by insulin [28,37,38]. The higher maternal values in IDDM may represent a deficiency of insulin action.…”

Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone

“…32 Insulin is the principal regulator of IGFBP-1 and is reported to inhibit hepatic IGFBP-1 synthesis. 33 Because of this property, IGFBP-1 is thought to play an important role in the regulation of IGF bioactivity. Therefore, the obesityrelated hyperinsulinaemia may decrease circulating concentrations of IGFBP-1, which can result in elevated free IGF-1 in obesity.…”

Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.

“…Another considerable proportion of changes in net protein balance was accounted for by the decrease in IGFBP-1 after rhGH. This protein is produced by the liver and both insulin (42) and rhGH (41) reduces IGFBP-1 levels, thus increasing the bioavailability of IGF-I.…”